{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T21:44:57Z","timestamp":1767649497020,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T00:00:00Z","timestamp":1753488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Studies investigating the long-term cellular immune response to SARS-CoV-2 mRNA vaccines in patients with inflammatory bowel disease (IBD) remain limited, particularly among those receiving immunosuppressive therapy. Methods: We prospectively evaluated humoral and cellular immune responses at short-term (4\u20136 weeks) and long-term (6\u201312 months) time points following SARS-CoV-2 mRNA vaccination in patients with IBD receiving anti-TNF agents, thiopurines, or combination therapy. We defined the short-term response as the measurement taken 4\u20136 weeks after the second vaccine dose and the long-term response as the measurement taken between 6 and 12 months after the first determination. A cohort of healthy controls was included for short-term comparative analysis. Results: At long-term follow-up, quantitative humoral responses were reduced in patients receiving anti-TNF monotherapy. In contrast, a reduced quantitative cellular response was found in the thiopurine (median 0.7 UI\/mL, p &lt; 0.05) and anti-TNF combo groups (median 0.4 UI\/mL, p &lt; 0.01) compared to anti-TNF monotherapy (median 2.2 UI\/mL). Conclusions: There was a robust long-term humoral and cellular response to vaccination, but a diminished quantitative cellular response in patients treated with thiopurines or combo therapy compared to anti-TNF monotherapy.<\/jats:p>","DOI":"10.3390\/cells14151156","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T07:57:24Z","timestamp":1753689444000},"page":"1156","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impaired Long-Term Quantitative Cellular Response to SARS-CoV-2 Vaccine in Thiopurine-Treated IBD Patients"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2867-7505","authenticated-orcid":false,"given":"Luis","family":"Mayorga Ayala","sequence":"first","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2721-3471","authenticated-orcid":false,"given":"Claudia","family":"Herrera-deGuise","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Esperalba","sequence":"additional","affiliation":[{"name":"Servei de Microbiologia, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Martinez-Gomez","sequence":"additional","affiliation":[{"name":"Servei de Medicina Preventiva i Epidemiologia, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"C\u00e9spedes Martinez","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2478-8923","authenticated-orcid":false,"given":"Xavier","family":"Serra Ruiz","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2580-0699","authenticated-orcid":false,"given":"Virginia","family":"Robles","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesto","family":"Lastiri","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0078-5464","authenticated-orcid":false,"given":"Zahira","family":"Perez","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Oller","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5584-3537","authenticated-orcid":false,"given":"Candela","family":"Fernandez-Naval","sequence":"additional","affiliation":[{"name":"Servei de Microbiologia, Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona (UAB), CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7340-2161","authenticated-orcid":false,"given":"M\u00f3nica","family":"Martinez-Gallo","sequence":"additional","affiliation":[{"name":"Servei d\u2019Immunologia, Hospital Universitari Vall d\u2019Hebron, Vall d\u2019Hebron Institut de Recerca (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesc","family":"Casellas","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-2292","authenticated-orcid":false,"given":"Natalia","family":"Borruel","sequence":"additional","affiliation":[{"name":"Unitat d\u2019Atenci\u00f3 Crohn-Colitis, Servei d\u2019Aparell Digestiu, Hospital Universitari Vall d\u2019Hebron, CP 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red, Enfermedades Hep\u00e1ticas y Digestivas, CIBEREHD, Instituto de Salud Carlos III, CP 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.cgh.2022.02.030","article-title":"Effectiveness and Durability of COVID-19 Vaccination in 9447 Patients With IBD: A Systematic Review and Meta-Analysis","volume":"20","author":"Jena","year":"2022","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/S2468-1253(22)00005-X","article-title":"COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): A multicentre, prospective, case-control study","volume":"7","author":"Alexander","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1136\/gutjnl-2021-324789","article-title":"Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD","volume":"70","author":"Kennedy","year":"2021","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S2468-1253(22)00274-6","article-title":"COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): A multicentre, prospective, case-control study","volume":"7","author":"Alexander","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_5","first-page":"1","article-title":"Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab","volume":"13","author":"Lin","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1136\/gutjnl-2022-327570","article-title":"Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic","volume":"72","author":"Kennedy","year":"2022","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S2468-1253(22)00389-2","article-title":"Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4\/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): An analysis of a prospective multicentre cohort study","volume":"8","author":"Liu","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1136\/annrheumdis-2021-221206","article-title":"Booster-dose SARS-CoV-2 vaccination in patients with autoimmune disease: A case series","volume":"81","author":"Connolly","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1038\/s41591-021-01507-2","article-title":"Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy","volume":"27","author":"Apostolidis","year":"2021","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41590-021-01122-w","article-title":"The T cell immune response against SARS-CoV-2","volume":"23","author":"Moss","year":"2022","journal-title":"Nat Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5780","DOI":"10.1002\/jmv.28063","article-title":"The long term vaccine-induced anti-SARS-CoV-2 immune response is impaired in quantity and quality under TNFalpha blockade","volume":"94","author":"Geisen","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1093\/ibd\/izac228","article-title":"Impact of Biologic Agents on the Immune Response Induced by the Additional Dose of SARS-CoV-2 Vaccine in Inflammatory Bowel Disease Patients","volume":"29","author":"Ramos","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1093\/ecco-jcc\/jjac048","article-title":"Cellular and Humoral Immune Responses to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease Patients","volume":"16","author":"Cerna","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/apt.17264","article-title":"Systemic and T cell-associated responses to SARS-CoV-2 immunisation in gut inflammation (STAR SIGN study): Effects of biologics on vaccination efficacy of the third dose of mRNA vaccines against SARS-CoV-2","volume":"57","author":"Woelfel","year":"2022","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/ibd\/izac193","article-title":"Higher Cell-Mediated Immune Responses in Patients With Inflammatory Bowel Disease on Anti-TNF Therapy After COVID-19 Vaccination","volume":"29","author":"Caldera","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1093\/ibd\/izac071","article-title":"The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy","volume":"28","author":"Li","year":"2022","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Qui, M., Le Bert, N., Chan, W.P.W., Tan, M., Hang, S.K., Hariharaputran, S., Sim, J.X.Y., Low, J.G.H., Ng, W., and Wan, W.Y. (2022). Favorable vaccine-induced SARS-CoV-2\u2013specific T cell response profile in patients undergoing immune-modifying therapies. J. Clin. Investig., 132.","DOI":"10.1172\/JCI159500"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00484","DOI":"10.14309\/ctg.0000000000000484","article-title":"Preserved SARS-CoV-2 Vaccine Cell-Mediated Immunogenicity in Patients With Inflammatory Bowel Disease on Immune-Modulating Therapies","volume":"13","author":"Boland","year":"2022","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_19","first-page":"712","article-title":"Robust SARS-CoV-2 antibody and T cell immunity following three COVID-19 vaccine doses in inflammatory bowel disease patients receiving anti-TNF or alternative treatments","volume":"73","author":"Zhang","year":"2023","journal-title":"Gut"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103175","DOI":"10.1016\/j.jaut.2024.103175","article-title":"mRNA-1273 vaccinated inflammatory bowel disease patients receiving TNF inhibitors develop broad and robust SARS-CoV-2-specific CD8+ T cell responses","volume":"144","author":"Duurland","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0140-6736(21)00527-4","article-title":"WHO International Standard for anti-SARS-CoV-2 immunoglobulin","volume":"397","author":"Kristiansen","year":"2021","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.medcli.2021.09.013","article-title":"Commercialized kits to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in health care workers","volume":"159","author":"Esperalba","year":"2022","journal-title":"Med. Clin."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1038\/s41591-023-02414-4","article-title":"SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease","volume":"29","author":"Barnes","year":"2023","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1016\/j.cell.2020.05.015","article-title":"Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals","volume":"181","author":"Grifoni","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1016\/j.cell.2020.09.038","article-title":"Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity","volume":"183","author":"Moderbacher","year":"2020","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104394","DOI":"10.1016\/j.jcv.2020.104394","article-title":"Comparison of four new commercial serologic assays for determination of SARS-CoV-2 IgG","volume":"128","author":"Cornelissen","year":"2020","journal-title":"J. Clin. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e3130","DOI":"10.1093\/cid\/ciaa1537","article-title":"Interferon-\u03b3 Release Assay for Accurate Detection of Severe Acute Respiratory Syndrome Coronavirus 2 T-Cell Response","volume":"73","author":"Murugesan","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1038\/s41590-023-01613-y","article-title":"Prior vaccination promotes early activation of memory T cells and enhances immune responses during SARS-CoV-2 breakthrough infection","volume":"24","author":"Painter","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00688","DOI":"10.14309\/ctg.0000000000000688","article-title":"Higher and Sustained Cell-Mediated Immune Responses After 3 Doses of mRNA COVID-19 Vaccine in Patients With Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy","volume":"15","author":"Caldera","year":"2024","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1128\/JVI.79.1.202-213.2005","article-title":"Role of Tumor Necrosis Factor Receptors in Regulating CD8 T-Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection","volume":"79","author":"Suresh","year":"2005","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1172\/JCI16432","article-title":"CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes","volume":"111","author":"Tiede","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_32","first-page":"396","article-title":"Early preservation of effector functions followed by eventual T cell memory depletion: A model for the delayed onset of the effect of thiopurines","volume":"58","author":"Goldstein","year":"2008","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.dld.2022.08.027","article-title":"Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study","volume":"55","author":"Macaluso","year":"2022","journal-title":"Dig. Liver Dis."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1156\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:16:35Z","timestamp":1760033795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/15\/1156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,26]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["cells14151156"],"URL":"https:\/\/doi.org\/10.3390\/cells14151156","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,7,26]]}}}